Twists and turns from "tumor in tumor" profiling: surveillance of chronic lymphocytic leukemia (CLL) leads to detection of a lung adenocarcinoma, whose genomic characterization alters the original hematologic diagnosis

Cold Spring Harb Mol Case Stud. 2021 Aug 2;7(4):a006089. doi: 10.1101/mcs.a006089. Print 2021 Aug.


Comprehensive characterization of somatic genomic alterations has led to fundamental shifts in our understanding of tumor biology. In clinical practice, these studies can lead to modifications of diagnosis and/or specific treatment implications, fulfilling the promise of personalized medicine. Herein, we describe a 78-yr-old woman under surveillance for long-standing untreated chronic lymphocytic leukemia (CLL). Molecular studies from a peripheral blood specimen revealed a TP53 p.V157F mutation, whereas karyotype and fluorescence in situ hybridization (FISH) identified a 17p deletion, trisomy 12, and no evidence of IGH-CCND1 rearrangement. Positron emission tomography-computed tomography scan identified multistation intra-abdominal lymphadenopathy and a pulmonary nodule, and subsequent pulmonary wedge resection confirmed the presence of a concurrent lung adenocarcinoma. Targeted next-generation sequencing of the lung tumor identified an EGFR in-frame exon 19 deletion, two TP53 mutations (p.P152Q, p.V157F), and, unexpectedly, a IGH-CCND1 rearrangement. Follow-up immunohistochemistry (IHC) studies demonstrated a cyclin D1-positive lymphoid aggregate within the lung adenocarcinoma. The presence of the TP53 p.V157F mutation in the lung resection, detection of an IGH-CCND1 rearrangement, and cyclin D1 positivity by IHC led to revision of the patient's hematologic diagnosis and confirmed the extranodal presence of mantle cell lymphoma within the lung mass, thus representing a "tumor in tumor." Manual review of the sequencing data suggested the IGH-CCND1 rearrangement occurred via an insertional event, whose size precluded detection by original FISH studies. Thus, routine imaging for this patient's known hematologic malignancy led to detection of an unexpected solid tumor, whose subsequent precision medicine studies in the solid tumor redefined the original hematological diagnosis.

Keywords: chronic lymphatic leukemia; hematological neoplasm; lung adenocarcinoma.

Publication types

  • Case Reports

MeSH terms

  • Adenocarcinoma of Lung / diagnosis*
  • Adenocarcinoma of Lung / genetics
  • Aged
  • Biomarkers, Tumor / genetics
  • Diagnostic Errors
  • Female
  • Gene Expression Profiling
  • Gene Rearrangement
  • High-Throughput Nucleotide Sequencing
  • Humans
  • In Situ Hybridization, Fluorescence
  • Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Lung Neoplasms / diagnosis*
  • Lung Neoplasms / genetics
  • Lymphoma, Mantle-Cell / diagnosis*
  • Lymphoma, Mantle-Cell / genetics
  • Neoplasms, Multiple Primary / diagnosis*
  • Neoplasms, Multiple Primary / genetics
  • Positron Emission Tomography Computed Tomography


  • Biomarkers, Tumor